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United States Patent ()fifice 2,693,465 Patented Nov. 2, 1954 PRQCESS 8FMANUFACTURE OF 6,7-DIHYDRO- SH-DIEENZ [c,e] AZEPINE AND DERIVATIVESRobert August Schmidt, Wellington, and Wilhelm Wenner, Upper Montciair,N. J., assignors to Hoflt'mann- La Roche Inc, Nutley, N. 3., acorporation of New Jersey No Drawing. Application April 20, 1953, SerialNo. 349,968

2 Claims. (Cl. 260-239) In Wenner U. S. Patent No. 2,619,484, there aredisclosed novel tricyclic amines, e. g.,6,7,-dihydro-5H-dibenz[c,e]azephine and derivatives thereof, useful intherapeutics to inhibit or reverse the physiological actions ofepinephrine. In that disclosure, the said tricyclic amines are made byreacting o,o'-bis-(bromomethyl)- biphenyl with ammonia or with a primaryamine. The instant invention relates to an alternative process formaking the same compounds, and broadly can be de scribed as comprisingthe steps of reducing diphenimide to form6,7-dihydro-5H-dibenz[c,e]azepine, and if desired, reacting the latterwith a lower alkyl halide or a lower alkenyl halide to introduce analiphatic substituent at the 6-position. A specific embodiment of theinvention comprises dehydrating diphenic acid to form diphenicanhydride, aminating the latter to produce diphenamic acid, removing onemol of ammonia therefrom to yield diphenimide, treating the latter withlithium aluminum hydride to yield 6,7-dihydro-5H-dibenz[c,e] azepine andreacting the latter with an allyl halide to form a hydrohalic acidaddition salt of 6allyl-6,7-dihydro-SH-dibenz [c,e] azepine.

The invention is further disclosed in the following example, which isillustrative but not limitative thereof.

Example 29 grams of diphenic acid were stirred in 900 cc. of aceticanhydride at 120" C. for one hour. The cooled mixture was filtered andwashed with acetic acid to give diphenic anhydride, colorless crystals,M. P. about 222-226 C.

24.11 grams of diphenic anhydride were mixed with 50 cc. of concentratedammonia. The mixture warmed up and cooling was applied, after which themixture was stirred till a clear solution formed and for 1% hoursafterward. The mixture was acidified and allowed to stand overnight.Water was added, initiating precipitation. The mixture was chilled andfiltered to yield diphenamic acid, a colorless solid, M. P. about 191193C.

23.5 grams of diphenamic acid were heated at 200 C. in an oil bath,first for about 20 hours at atmospheric pressure and then for about 10hours at about mm.

Melting points were taken at intervals in order to gain an idea of theextent of reaction. The final residue was boiled with alcohol but sincethe solid exhibited insufiicient solubility in the hot solvent, themixture was filtered. The residue consisted of tan crystals, M. P. about220-221 C., and the filtrate on cooling gave an additional crop of tancrystals, M. P. about 21922l C. The two materials were identical andconsisted of diphenimide.

5.58 grams of diphenimide were placed in a Soxhlet thimble and extractedfor about 3 days with a boiling mixture of 9.0 g. of lithium aluminumhydride in 600 cc. of sodium-dried ether. Excess lithium aluminumhydride was then decomposed cautiously with water and the mixture wasfiltered through a filter aid by suction. The filtrate consisted of twolayers. The ether layer was separated and dried with anhydrous potassiumcarbonate and acidified with alcoholic hydrochloric acid togive-6,7-dihydro-5H-dibenz[c,elazephine hydrochloride, M. P. about287289 C.

One gram of 6,7-dihydro-5H-dibenz[c,elazepine hydrochloride wasdissolved in water, made alkaline with concentrated ammonia, and theresultant base extracted twice with benzene. The benzene layers werecombined, dried with anhydrous potassium carbonate, and mixed with 0.261g. of allyl bromide at 25-30 C. The reaction solution became turbidwithin a few minutes and showed a considerable crystalline deposit afterstanding 3 /2 days. The mixture was warmed 1% hours on the steam bath ina loosely-stoppered flask, then cooled and filtered. The filtrate waswashed twice with water and the benzene layer evaporated at diminishedpressure. The liquid residue was dissolved in alcohol, shaken withcharcoal and filtered. Addition to the filtrate of 0.3 gram of per centphosphoric acid in alcohol gave a clear solution which, when seeded andrubbed, yielded 6-allyl-6,7-dihydro-5H-dibenz[c,e]azepine phosphate, M.P. about 2l1-215 C. with decomposition.

We claim:

1. A process which comprises reacting diphenimide with lithium aluminumhydride and treating the reduction product with a reagent selected fromthe class consisting of lower alkyl halides and lower alkenyl halides.

2. A process of making 6,7-dihydro-5H-dibenz[c,e] azepine whichcomprises reducing diphenimide with lithium aluminum hydride.

References Cited in the file of this patent UNITED STATES PATENTS NumberName Date 2,520,264 1 Walter Aug. 29, 1950 2,619,484 Wenner Nov. 25,1952 OTHER REFERENCES Morrison et al., J. Chem. Soc., vol. 1951, pp.952-5.

2. A PROCESS OF MAKING 6,7-DIHYDRO-5H-DIBENZ(C,E) AZEPINE WHICH COMPRISES REDUCING DIPHENIMIDE WITH LITHIUM ALUMINUM HYDRIDE. 